目的:探讨静脉溶栓序贯丁苯酞治疗轻中度急性缺血性脑卒(acute ischemic stroke, AIS)中后早期神经功能恶化(early neurological function deterioration, END)影响的相关性。方法:连续纳入2019年1月至2021年12月期间在云南省滇南中心医院卒中单元进行静脉溶栓的轻中度急性缺血性卒中(acute ischemic stroke, AIS)患者。收集患者临床、影像学和实验室检查资料。早期神经功能恶化(neurological function deterioration, END)定义为急性缺血性脑卒中r-tPA静脉溶栓后7天内,美国国立卫生研究院卒中量表(National Institutes of Health Stroke Scale, NIHSS)评分最高分较入院时增加≥2分,或运动功能评分 ≥ 1分。应用多变量logistic回归分析确定静脉溶栓序贯丁苯酞治疗与END的是否发生独立相关性。结果:共纳入146例AIS患者,共有14例(9.59%)患者发生END。END组与非END组在高脂血症史、心房颤动史、收缩压、舒张压及OSCP分型方面差异有统计学意义(P均<0.05)。两组患者在人口统计学、其余血管危险因素、实验室检查结果、ONT、基线NIHSS评分、FAZEKAS分级及是否使用丁苯酞等临床资料方面均无统计学差异。单因素分析筛选出轻中度AIS静脉溶栓后END与收缩压、舒张压、高脂血症史及OSCP分型有关,差异有统计学意义。分层分析丁苯酞使用与否与END无相关性。最后通过多因素Logistic回归分析,调整收缩压、舒张压、高脂血症史及OSCP分型后,是否使用丁苯酞与是否发生END在总体人群、女性及男性方面均无相关性。结论:是否使用丁苯酞与轻中度AIS患者静脉溶栓后7天发生END无相关性,丁苯酞不能改善7天内轻中度AIS r-tPA静脉溶栓患者的预后。 Objective: To investigate the association between early neurological function degeneration (END) after intravenous thrombolysis sequentially Butylphthalide administration in mild to moderate acute ischemic stroke (AIS). Method: Patients with mild to moderate AIS who underwent intrave-nous thrombolysis at the stroke unit of Yunnan Center Hospital between January 2019 and Decem-ber 2021 were consecutively enrolled. Data on patients’ clinical, radiographic, and laboratory ex-aminations were collected. Early neurological deterioration (end) was defined as an increase of ≥ 2 points in the maximum National Institutes of Health Stroke Scale (NIHSS) score, or ≥ 1 point in the motor function score within 7 days after intravenous thrombolysis with r-tPA for acute ischemic stroke. Multivariable logistic regression analysis was applied to determine whether the independ-ent association of intravenous thrombolysis sequential Butylphthalide treatment and end occurred. Results: A total of 146 AIS patients were included, and a total of 14 (9.59%) patients developed END. There were significant differences between END and non END groups in hyperlipidemia history, atrial fibrillation history, systolic blood pressure, diastolic blood pressure and oscp classification (all P < 0.05). There were no statistically significant differences between the two groups in terms of de-mographics, remaining vascular risk factors, laboratory findings, ont, baseline NIHSS score, Fazekas grade, and clinical data regarding the use or not of Butylphthalide. In univariate analysis, END was related to systolic blood pressure, diastolic blood pressure, history of hyperlipidemia and oscp clas-sification in mild to moderate AIS after intravenous thrombolysis with statistical significance. Strat-ified analysis of the presence or absence of Butylphthalide use was not associated with END. Finally by multivariate logistic regression analysis, adjusted for systolic blood pressure, diastolic blood pressure, history of hyperlipidemia and oscp after subtyping, whether Butylphthalide use was as-sociated with developing end was not available in the overall population, nor in women and men. Conclusion: Whether the use of Butylphthalide is associated with the development of END 7 days after intravenous thrombolysis in patients with mild moderate AIS was not determined, and Bu-tylphthalide did not improve outcome in patients with mild moderate AIS r-tPA intravenous thrombolysis within 7 days.
目的:探讨静脉溶栓序贯丁苯酞治疗轻中度急性缺血性脑卒(acute ischemic stroke, AIS)中后早期神经功能恶化(early neurological function deterioration, END)影响的相关性。方法:连续纳入2019年1月至2021年12月期间在云南省滇南中心医院卒中单元进行静脉溶栓的轻中度急性缺血性卒中(acute ischemic stroke, AIS)患者。收集患者临床、影像学和实验室检查资料。早期神经功能恶化(neurological function deterioration, END)定义为急性缺血性脑卒中r-tPA静脉溶栓后7天内,美国国立卫生研究院卒中量表(National Institutes of Health Stroke Scale, NIHSS)评分最高分较入院时增加≥2分,或运动功能评分 ≥ 1分。应用多变量logistic回归分析确定静脉溶栓序贯丁苯酞治疗与END的是否发生独立相关性。结果:共纳入146例AIS患者,共有14例(9.59%)患者发生END。END组与非END组在高脂血症史、心房颤动史、收缩压、舒张压及OSCP分型方面差异有统计学意义(P均<0.05)。两组患者在人口统计学、其余血管危险因素、实验室检查结果、ONT、基线NIHSS评分、FAZEKAS分级及是否使用丁苯酞等临床资料方面均无统计学差异。单因素分析筛选出轻中度AIS静脉溶栓后END与收缩压、舒张压、高脂血症史及OSCP分型有关,差异有统计学意义。分层分析丁苯酞使用与否与END无相关性。最后通过多因素Logistic回归分析,调整收缩压、舒张压、高脂血症史及OSCP分型后,是否使用丁苯酞与是否发生END在总体人群、女性及男性方面均无相关性。结论:是否使用丁苯酞与轻中度AIS患者静脉溶栓后7天发生END无相关性,丁苯酞不能改善7天内轻中度AIS r-tPA静脉溶栓患者的预后。
卒中,静脉溶栓,早期神经功能恶化,丁苯酞
Man Shen1, Fan Wang2, Wanqing Tao3
1Office of Medical Quality Control, Southern Central Hospital of Yunnan Province, Honghe Yunnan
2Medical Department, Southern Central Hospital of Yunnan Province, Honghe Yunnan
3Department of Neurology, Southern Central Hospital of Yunnan Province, Honghe Yunnan
Received: Nov. 23rd, 2022; accepted: Dec. 16th, 2022; published: Dec. 23rd, 2022
Objective: To investigate the association between early neurological function degeneration (END) after intravenous thrombolysis sequentially Butylphthalide administration in mild to moderate acute ischemic stroke (AIS). Method: Patients with mild to moderate AIS who underwent intravenous thrombolysis at the stroke unit of Yunnan Center Hospital between January 2019 and December 2021 were consecutively enrolled. Data on patients’ clinical, radiographic, and laboratory examinations were collected. Early neurological deterioration (end) was defined as an increase of ≥ 2 points in the maximum National Institutes of Health Stroke Scale (NIHSS) score, or ≥ 1 point in the motor function score within 7 days after intravenous thrombolysis with r-tPA for acute ischemic stroke. Multivariable logistic regression analysis was applied to determine whether the independent association of intravenous thrombolysis sequential Butylphthalide treatment and end occurred. Results: A total of 146 AIS patients were included, and a total of 14 (9.59%) patients developed END. There were significant differences between END and non END groups in hyperlipidemia history, atrial fibrillation history, systolic blood pressure, diastolic blood pressure and oscp classification (all P < 0.05). There were no statistically significant differences between the two groups in terms of demographics, remaining vascular risk factors, laboratory findings, ont, baseline NIHSS score, Fazekas grade, and clinical data regarding the use or not of Butylphthalide. In univariate analysis, END was related to systolic blood pressure, diastolic blood pressure, history of hyperlipidemia and oscp classification in mild to moderate AIS after intravenous thrombolysis with statistical significance. Stratified analysis of the presence or absence of Butylphthalide use was not associated with END. Finally by multivariate logistic regression analysis, adjusted for systolic blood pressure, diastolic blood pressure, history of hyperlipidemia and oscp after subtyping, whether Butylphthalide use was associated with developing end was not available in the overall population, nor in women and men. Conclusion: Whether the use of Butylphthalide is associated with the development of END 7 days after intravenous thrombolysis in patients with mild moderate AIS was not determined, and Butylphthalide did not improve outcome in patients with mild moderate AIS r-tPA intravenous thrombolysis within 7 days.
Keywords:Apoplexy, Intravenous Thrombolysis, Early Neurological Deterioration, Butylphthalide
Copyright © 2022 by author(s) and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).
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重组组织型纤溶酶原激活剂(rt-PA)可降低脑梗死的残疾率和死亡率已得到世界的公认,但r-tPA会触发并升级炎症反应的瀑布效应 [
连续纳入2019年1月至2020年12月期间云南省滇南中心医院卒中单元的进行静脉溶栓AIS患者。纳入标准:1) 符合《中国急性缺血性脑卒中诊治指南2018》AIS诊断标准,并且经头颅CT或MRI证实;2) 溶栓后7天NIHSS评分及其分类 [
收集所有符合纳排标准的轻中度AIS患者的人口统计学资料(年龄、性别)、血管危险因素(高血压、高脂血症、糖尿病、心房颤动、卒中史、吸烟、饮酒)、入院时血压(收缩压、舒张压)、基线实验室检查[血小板计数(PLT)、WBC、中性粒细胞/淋巴细胞比值(neutrophil to lymphocyte ratio, NLR)]、RDW (红细胞分布宽度)、淋巴细胞计数、尿酸、入院微量血糖、白蛋白、甘油三脂、低密度脂蛋白胆固醇、同型半胱氨酸(Hcy)、TOAST分型、OSCP分型、FAZEKAS分级和ONT。
两组患者均在r-PA静脉溶栓后接受丁苯酞氯化钠注射液或丁苯酞软胶囊(石药集团恩必普药业有限公司)进行7 d治疗。其余治疗按照脑梗死标准治疗。
END定义为静脉溶栓后7天NIHSS评分相较于溶栓后最好的神经功能状态评分增加≥2分 [
应用基于R软件的易侕统计软件3.0 (https://www.empowerstats.com/)进行统计分析。符合正态分布的定量资料采用均数 ± 标准差(x ± s)表示,组间比较采用两独立样本均数的t检验;不符合正态分布的定量资料采用中位数和四分位数[M(P25, P75)]表示,组间比较采用Mann-Whitney U检验;定性资料采用例(百分比)表示,组间比较采用卡方检验或Fisher确切概率法,Pearson相关性检验分析WBC与基线NIHSS评分的相关性。对结局指标进行logistic多元回归分析,调整基线有差异的变量,分析WBC与END的关系。
研究期间共纳入146例符合要求的轻中度AIS患者,男性94例(64.38%),平均年龄61.29 (标准差11.52岁);END组14例(9.59%),非END组132例(90.41%)。
END组与非END组在高脂血症史、心房颤动史、收缩压、舒张压及OSCP分型方面差异有统计学意义(P均<0.05;表1)。两组患者在人口统计学、其余血管危险因素、实验室检查结果、ONT、基线NIHSS评分、FAZEKAS分级及是否使用丁苯酞等临床资料方面均无统计学差异(见表1)。
变量 | 非END (132) | END (14) | t值、χ2值或Z值 | P值* | |
---|---|---|---|---|---|
人口统计学 | |||||
年龄[岁,Mean (SD)] | 61.29 (11.52) | 63.00 (13.36) | 0.14 (−0.41, 0.69) | 0.603 | |
男性(n, %) | 88 (66.67%) | 6 (42.86%) | 0.49 (−0.06, 1.05) | 0.077 | |
脑血管危险因素(n, %) | |||||
高血压史 | 70 (53.03%) | 7 (50.00%) | 0.06 (−0.49, 0.61) | 0.829 | |
2型糖尿史 | 22 (16.67%) | 4 (28.57%) | 0.29 (−0.26, 0.84) | 0.268 | |
高脂血症史 | 2 (1.52%) | 2 (14.29%) | 0.49 (−0.07, 1.04) | 0.005 | |
吸烟史 | 61 (46.21%) | 4 (28.57%) | 0.37 (−0.18, 0.92) | 0.207 | |
饮酒史 | 37 (28.03%) | 2 (14.29%) | 0.34 (−0.21, 0.89) | 0.269 | |
心房颤动史 | 5 (3.79%) | 2 (14.29%) | 0.37 (−0.18, 0.93) | 0.08 | |
卒中史 | 18 (13.74%) | 2 (14.29%) | 0.02 (−0.54, 0.57) | 0.955 | |
入院血压[mmHg, Mean (SD)] | |||||
收缩压 | 152.97 (22.14) | 165.64 (23.83) | 0.55 (−0.00, 1.11) | 0.045 | |
舒张压 | 92.92 (15.75) | 104.29 (26.08) | 0.53 (−0.03, 1.08) | 0.018 | |
ONT [分钟,Mean (SD)] | 134.15 (63.56) | 162.21 (69.38) | 0.42 (−0.13, 0.97) | 0.122 | |
RDW | 43.14 (4.06) | 41.61 (2.49) | 0.45 (−0.10, 1.01) | 0.171 | |
PLT [×109/L, Mean (SD)] | 232.71 (58.39) | 204.14 (70.99) | 0.44 (−0.11, 0.99) | 0.091 | |
WBC [×109/L, Mean (SD)] | 8.25 (2.54) | 9.46 (3.06) | 0.43 (−0.12, 0.98) | 0.1 | |
NLR | 1.99 (0.50~15.14) | 2.49 (0.80~19.94) | 0.35 (−0.21, 0.90) | 0.179 | |
尿酸[mmol/L, Mean (SD)] | 353.56 (102.45) | 341.86 (105.25) | 0.11 (−0.44, 0.66) | 0.686 | |
入院血糖[mmol/L, Median (Min-Max)] | 7.03 (2.18~26.48) | 8.73 (5.13~26.66) | 0.44 (−0.11, 0.99) | 0.09 | |
白蛋白[mmol/L, Mean (SD)] | 40.77 (3.70) | 40.95 (4.00) | 0.05 (−0.52, 0.62) | 0.862 | |
甘油三脂[mmol/L, Median (Min-Max)] | 1.62 (0.49~7.76) | 1.97 (0.38~4.42) | 0.06 (−0.56, 0.67) | 0.739 | |
低密度脂蛋白胆固醇 [mmol/L, Mean (SD)] | 2.81 (0.83) | 3.08 (0.89) | 0.31 (−0.30, 0.93) | 0.309 | |
HCY [mmol/L, Median (Min-Max)] | 15.97 (12.57) | 12.15 (9.50~33.80) | 0.08 (−0.92, 1.08) | 0.885 | |
基线NIHSS评分 [分,Median (Min-Max)] | 3.50 (0.00~14.00) | 5.00 (3.00~11.00) | 0.30 (−0.25, 0.85) | 0.094 | |
TOAST分型 | 0.47 (−0.09, 1.02) | 0.672 | |||
大动脉 | 62 (46.97%) | 9 (64.29%) | |||
心源性 | 9 (6.82%) | 1 (7.14%) | |||
小动脉 | 42 (31.82%) | 2 (14.29%) | |||
不明原因 | 13 (9.85%) | 1 (7.14%) | |||
其他原因 | 6 (4.55%) | 1 (7.14%) | |||
OSCP分型 | 0.74 (0.18, 1.30) | 0.026 | |||
完全前循环 | 7 (5.30%) | 4 (28.57%) | |||
部分前循环 | 90 (68.18%) | 6 (42.86%) | |||
后循环 | 30 (22.73%) | 3 (21.43%) | |||
腔隙性脑梗死 | 1 (0.76%) | 0 (0.00%) | |||
部分前循环 + 后循环 | 4 (3.03%) | 1 (7.14%) | |||
FAZEKAS | 0.20 (−0.35, 0.75) | 0.914 | |||
0 | 43 (32.58%) | 4 (28.57%) | |||
1 | 47 (35.61%) | 5 (35.71%) | |||
2 | 28 (21.21%) | 4 (28.57%) | |||
3 | 14 (10.61%) | 1 (7.14%) | |||
丁苯酞 | 36 (27.27%) | 3 (21.43%) | 0.14 (−0.41, 0.69) | 0.638 | |
表1. END组与非END组人口统计学和基线临床资料比较
表中结果:Mean (SD) Median (Min-Max)/N(%);P值*:如是连续变量,用Kruskal Wallis秩和检验得出,如计数变量有理论数 < 10,用Fisher精确概率检验得出。
单因素发现,结局变量是否发生END与收缩压、舒张压、高脂血症史及OSCP分型有关,差异有统计学意义(见表2)。
变量 | 结局(是否发生END) | β (95% CI) P值/OR (95% CI) P值 |
---|---|---|
男 | 94 (64.38%) | 2.67 (0.87, 8.16) 0.0857 |
年龄 | 61.45 ± 11.67 | 1.01 (0.97, 1.06) 0.6008 |
BMI | 23.39 ± 4.05 | 1.02 (0.89, 1.17) 0.7489 |
收缩压 | 154.19 ± 22.54 | 1.02 (1.00, 1.05) 0.0500 |
舒张压 | 94.02 ± 17.23 | 1.03 (1.00, 1.06) 0.0332 |
高血压史 | 77 (52.74%) | 0.89 (0.29, 2.67) 0.8291 |
2型糖尿史 | 26 (17.81%) | 2.00 (0.57, 6.96) 0.2758 |
高脂血症史 | 4 (2.74%) | 10.83 (1.40, 83.92) 0.0225 |
吸烟史 | 65 (44.52%) | 0.47 (0.14, 1.56) 0.2152 |
饮酒史 | 39 (26.71%) | 0.43 (0.09, 2.00) 0.2814 |
房颤史 | 7 (4.79%) | 4.23 (0.74, 24.20) 0.1047 |
卒中史 | 20 (13.79%) | 1.05 (0.22, 5.07) 0.9552 |
基线NIHSS评分 | 4.80 ± 3.44 | 1.08 (0.93, 1.25) 0.3376 |
ONT | 136.84 ± 64.42 | 1.01 (1.00, 1.02) 0.1257 |
RDW | 42.99 ± 3.96 | 0.90 (0.77, 1.05) 0.1658 |
PLT | 229.97 ± 60.03 | 0.99 (0.98, 1.00) 0.0929 |
WBC | 8.37 ± 2.61 | 1.16 (0.97, 1.40) 0.1063 |
淋巴细胞计数 | 2.41 ± 1.05 | 0.88 (0.51, 1.54) 0.6655 |
NLR | 2.68 ± 2.46 | 1.14 (0.98, 1.34) 0.0949 |
RPR | 0.25 ± 0.51 | 1.17 (0.53, 2.59) 0.6910 |
尿酸 | 352.44 ± 102.41 | 1.00 (0.99, 1.00) 0.6836 |
入院血糖 | 8.77 ± 4.86 | 1.09 (0.99, 1.19) 0.0717 |
白蛋白 | 40.78 ± 3.71 | 1.01 (0.87, 1.18) 0.8612 |
甘油三脂 | 1.96 ± 1.26 | 1.04 (0.65, 1.68) 0.8588 |
低密度脂蛋白胆固醇 | 2.83 ± 0.84 | 1.44 (0.72, 2.87) 0.3068 |
HCY | 16.01 ± 12.47 | 1.01 (0.93, 1.08) 0.8836 |
OSCP分型 | ||
完全前循环 | 11 (7.53%) | 参照组 |
部分前循环 | 96 (65.75%) | 0.12 (0.03, 0.51) 0.0045 |
后循环 | 33 (22.60%) | 0.17 (0.03, 0.97) 0.0455 |
腔隙性脑梗死 | 1 (0.68%) | 0.00 (0.00, Inf) 0.9918 |
部分前循环 + 后循环 | 5 (3.42%) | 0.44 (0.04, 5.40) 0.5189 |
FAZEKAS | ||
0 | 47 (32.19%) | 参照组 |
1 | 52 (35.62%) | 1.14 (0.29, 4.54) 0.8487 |
2 | 32 (21.92%) | 1.54 (0.35, 6.65) 0.5661 |
3 | 15 (10.27%) | 0.77 (0.08, 7.45) 0.8198 |
表2. END的单因素分析
根据单因素分析结果,将是否使用丁苯酞作为自变量,是否发生END作为应变量,调整收缩压、舒张压、高脂血症史及OSCP分型后按性别进行分层分析(见表3)显示,分层后是否使用丁苯酞与是否发生END不存在相关性(P值均大于0.05)。
性别 | N | END [OR (95% CI) P值] |
---|---|---|
男 | 94 | 0.17 (0.01, 2.96) 0.2217 |
女 | 52 | 0.83 (0.10, 6.54) 0.8579 |
表3. 分层分析
分层分析中,男女性别之间存在不存在差异,以溶栓后7天是否发生END为结果变量,是否使用丁苯酞为暴露变量;logistic多元回归分析(见表4)模型一在调整基线收缩压;舒张压;高脂血症史;模型二在调整OSCP分型;模型三在调整收缩压;舒张压;高脂血症史及OSCP分型上亦未得出阳性结果;三个模型均呈是否使用丁苯酞与是否发生END在总体人群、女性及男性无相关性(P值均大于0.05)。
Model | 男 | 女 | Total |
---|---|---|---|
模型一 | 0.32 (0.03, 3.85) 0.3664 | 1.36 (0.22, 8.49) 0.7418 | 0.73 (0.18, 3.05) 0.6705 |
模型二 | 0.18 (0.01, 2.89) 0.2269 | 0.90 (0.13, 6.06) 0.9144 | 0.56 (0.13, 2.41) 0.4358 |
模型三 | 0.17 (0.01, 2.96) 0.2217 | 0.83 (0.10, 6.54) 0.8579 | 0.41 (0.08, 2.09) 0.2843 |
表4. logistic多元回归分析
表中数据:OR (95% CI) P值。
约10%~40% [
本研究首先通过单因素分析筛选出轻中度AIS静脉溶栓后END与收缩压、舒张压、高脂血症史及OSCP分型有关,差异有统计学意义。分层分析丁苯酞使用与否与END无相关性。最后通过多因素Logistic回归分析,调整收缩压、舒张压、高脂血症史及OSCP分型后,是否使用丁苯酞与是否发生END在总体人群、女性及男性方面无相关性。与张宝瑞 [
综上所述,是否使用丁苯酞与轻中度AIS患者静脉溶栓后7天发生END无相关性,丁苯酞不能改善7天内轻中度AIS r-tPA静脉溶栓患者的预后。本研究的局限性:1) 回顾性研究且样本量相对偏小,进行回归分析时容易产生偏差及偏倚,同时导致样本代表性降低;2) 样本量不够大,且仅针对部分项目进行统计分析,不能代表所有AISr-tPA静脉溶栓并使用丁苯酞人群和所有影响因素;3) 因样本量有限,未针对OCSP分型、TOAST分型进行亚组分析。
所有作者均声明不存在利益冲突。
沈 曼,王 凡,陶万清. 轻中度急性缺血性脑卒中静脉溶栓序贯丁苯酞治疗与早期神经功能恶化影响的相关性Association between Intravenous Thrombolysis and Early Neurological Deterioration Effects of Sequential Butylphthalide Treatment in Mild to Moderate Acute Ischemic Stroke[J]. 医学诊断, 2022, 12(04): 302-309. https://doi.org/10.12677/MD.2022.124049